Joseph A. Albanese, director of Analytical Strategy and Compliance at Janssen Research and Development, LLC

Joseph A. Albanese

Scientist wearing blue gloves pointing at charts and graphs on a paper document while analyzing medical research data using a tablet in a laboratory setting, with a microscope and beakers nearby | Image Credit: ©crizzystudio – stock.adobe.com

A specification as previously defined is a list of tests, references to analytical procedures, and appropriate acceptance criteria (1). The specification establishes the methodology to be applied and the corresponding acceptance criteria to which a drug substance or drug product must conform to be considered acceptable for its intended use. Conformance to specifications means that the drug substance and/or drug product meets the specified acceptance criteria when tested following the test procedure contained within the specification. Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities as conditions of market authorization. Specifications are foundational to a robust control strategy for all components of a finished dosage form. In this article, the authors consider both the method and acceptance criteria components of the specification.

Specification Equivalence: A Practical Approach to Method and Acceptance Criteria Equivalence

Methods included in the specification must be validated and/or verified as described in current regulatory and compendial guidance documents. Methods are either used for release testing purposes or to detect changes in quality attributes over time (i.e., for stability testing). Also, as noted in the previous paper (1), if compendial methods for compendial articles are not used, the in-house method is defined as an alternate method to the official method per the regulations.

Various regulations are applicable when establishing method equivalency, including those from health authorities, compendial standards, and the International Council for Harmonisation (ICH) standards. The ICH Q2 document (2) describes the specifics regarding analytical method validation requirements, and the complementary ICH Q14 (3) describes the scientific and risk-based approaches for analytical procedure development and maintenance. It is critical to develop and validate an analytical method that is fit for purpose, which makes it vital to understand the intended use of the method prior to initiating any work. The intended use of a method is typically described in an analytical target profile (ATP). The ATP provides the basis for the required method development and subsequent method validation parameters per ICH Q2.

An option during method development is to define the method operable design regions (MODRs), which is a type of quality by design (QbD) for methods. Defining a MODR provides flexibility in an individual method, such that the operating ranges provided in the method are larger than the standard single points. Methods compared with a MODR cannot be theoretically compared unless there is overlap in their MODR design space. If there is no overlap in design space, an experimental equivalence study must be performed.

Methods may be developed internally or obtained from external sources, such as compendial monographs or other vendors/suppliers. During the lifecycle of a material, there will be method changes for any number of reasons, such as manufacturing changes, discontinuation of technology, automation introduction, and method modernization. The significance of the changes to the method and a review of the approved marketing authorization filing by the relevant health authorities must be considered. A change that impacts the method in the approved marketing dossier must be submitted to the health authorities for some level of approval prior to implementation.

Any changes to internal documents, whether or not they impact the filed dossier, must be managed under a change control process, required of each company as part of good manufacturing practices (GMPs). The change control process must include a step for the company’s regulatory department to review the changes and determine the impact, if any, to the filed dossier(s). If there is an impact to the filed dossier(s), the company’s regulatory department must submit the method to the relevant health authorities, and there must be a hold on implementation of the new method until the required filings are completed and approvals granted. During this process, the change(s) to the method will be reviewed and approved by the relevant health authorities. As part of this review, the reviewers may evaluate how the equivalency or superiority of the new method was established relative to the originally approved method.

Equivalency studies are performed to demonstrate that results generated using either the original analytical method or the proposed modified method, alternative method, or fully new method, yield insignificant differences in accuracy and precision, meaning that equivalent results are produced using either analytical procedure, and the same accept or reject decision is reached. 

) <1010> (4) presents numerous methods and statistical tools to design, execute, and evaluate equivalency protocols and data generated in these protocols. While the chapter is a valuable educational tool, it requires a proficient understanding of statistics to apply it well and, in many cases, may be more than is required in typical pharmaceutical analytical laboratories. With a deep knowledge of the methods being evaluated and the material or product being tested, basic statistical tools (e.g., mean, standard deviation, pooled standard deviation, evaluation of data generated against historical data, and comparison of data against approved specifications) may be sufficient to determine method equivalency or lack thereof. Equivalence of more complicated methods, such as methods that require the use of modeling will most likely require more sophisticated evaluation. Ultimately, the value in determining specification equivalence is the ability for a bio/pharmaceutical company to reduce analytical testing by choosing to perform one method to ensure compliance with other equivalent methods. If the methods under consideration are compendial, the outcome may be considered an internal or in-house harmonization of the various pharmacopoeial test methods.

Gail Reed is senior scientist with Johnson & Johnson; Joseph A. Albanese is the managing director and consultant with Albanese Consulting, LLC; Yelena Ionova is senior manager, Data Strategy and Analytics with Redica Systems; and J. Mark Wiggins is owner and compendial consultant with Global Pharmacopoeia Solutions, LLC.

BioPharm International®/Pharmaceutical Technology®/Pharmaceutical Technology® Europe

When referring to this article, please cite it as Reed, G.; Albanese, J.A.; Ionova, Y.; and Wiggins, J. M. Specification Equivalence: A Practical Approach to Method and Acceptance Criteria Equivalence. 

Pharmaceutical Technology Quality and Regulations

Articles

Specifications are critical quality standards for drug substances and products, ensuring they meet acceptance criteria for intended use. Methods within specifications must be validated and fit for purpose, with flexibility provided by defining method operable design regions (MODRs). Changes to methods require regulatory approval and adherence to change control processes. Equivalency studies ensure modified methods yield equivalent results to original methods, facilitating internal harmonization and reducing analytical testing. Understanding statistical tools is essential for evaluating method equivalency, particularly for complex methods requiring sophisticated evaluation.

The authors propose a streamlined, efficient approach to determining specification equivalence that starts with a paper-based assessment of the methods and progresses to a data assessment for the methods under evaluation.

A businessman pointing at a compliance icon with a technological business data network in the background, representing regulatory standards | Image Credit: ©AhmadTriwahyuutomo - stock.adobe.com

A specification is defined by the International Council for Harmonisation (ICH) documents Q6A and Q6B (1,2) as a list of tests, references to analytical procedures, and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described. A specification establishes the set of attributes and their associated criteria to which an excipient, drug substance or drug product should conform to be considered acceptable for its intended use. Conformance to specifications means that the excipient, drug substance, and/or drug product, when tested according to the listed analytical procedures, will meet the listed acceptance criteria. The guidance documents go on to indicate that specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities as conditions of approval. Specifications are foundational to a robust control strategy for all components of a finished dosage form.

Many bio/pharmaceutical companies find themselves trying to meet specifications for an excipient, drug substance and drug product that may have different tests and acceptance criteria in different regions or countries around the world. Companies can establish scientific rationale that methods are equivalent for a specific attribute (test) on the material’s specification, and then when tested, the material will comply with the acceptance criteria for all applicable regions. This risk-based approach is often used by companies to reduce the testing burden for release and stability laboratories. However, companies struggle with establishing equivalence for different methods used for the same attribute on the specification. Oftentimes, the acceptance criteria for the methods are not suitably considered in the evaluation.

As an example, pharmaceutical manufacturers often try to determine specification equivalence for materials that come from different sources. The different sources could be the “same” material produced at two or more sites or made by two or more suppliers. While the comparison of specifications may appear to be a straightforward exercise, the details of the differences for both the analytical procedures and the acceptance criteria make the determination far more complicated. Specification equivalence is essential to determining if two different analytical procedures produce the same results for a given substance or product regardless of the manufacturing site. Specification equivalence is the first step in assessing the potential differences for materials from different sources. Once the analytical assessment is completed; a manufacturing assessment may also be required.

This series of papers intends to offer a practical approach to the concept of specification equivalence, first defining key terms used in the specification evaluation process in this paper. Subsequent papers will take a deeper dive into method equivalence and acceptance criteria equivalence which results in a process leading to a scientific decision on specification equivalence for a given attribute on a material specification. The last paper of the series will focus on the steps needed to perform specification equivalence for compendial materials where the respective monographs in the world’s pharmacopeia may not be harmonized.

Advances in technology, new regulatory requirements, and manufacturing processing changes are some of the potential reasons that there is a change to an analytical procedure or to the associated acceptance criteria. It is recognized by the health authorities that changes will occur in the lifetime of a material/product and there are pathways to make these changes with the impacted regulatory agencies. These pathways require suitable documentation to demonstrate that the changes being made continue to ensure suitable quality pharmaceutical substances and products for the patients. It also can provide a business opportunity to “harmonize specifications” and minimize redundant testing especially for multi-market products.

Specification equivalence can be defined in a way that is generally consistent with that of method equivalence published by Chambers (3) but is more fundamentally based upon the Pharmacopoeial Discussion Group (PDG) definition for harmonization, which is when a pharmaceutical substance or product tested by the harmonized procedure yields the same results and the same accept/reject decision is reached (4). The authors believe that adapting the PDG definition to include non-compendial methods provides for the most straightforward approach to determine specification equivalence. Additionally, specification equivalence draws on the concept of “harmonization by attribute”, which is an approach established by the PDG when an entire monograph (i.e., specification for a material) could not be harmonized. The PDG focused on the individual attributes that could be harmonized. The same is true for specification equivalence. Companies can go attribute by attribute to do a risk assessment of the methods and their acceptance criteria to ensure the same accept/reject decision is reached. Specification Equivalence is illustrated in 

. The benefit of re-defining this approach for specification equivalence is to minimize the use of cumbersome statistical techniques that can confound the analysis and to bring more emphasis to the acceptance criteria for the specific attribute.

Figure 1. Specification Equivalence by Attribute. (Figure courtesy of the authors)

The challenge of determining equivalency lies in the components of the specification, namely the analytical procedures and the acceptance criterion for the method. The differences encountered in both analytical procedures and the acceptance criterion can rapidly confound a straightforward approach to determine equivalency. In this series of papers, the authors examine all the parts of a specification and the role each plays in determining specification equivalence. The authors will offer a streamlined process to achieve a decision on specification equivalence, including a simple flow chart assessment for both the analytical procedure and its associated acceptance criteria. These flow charts could be used in a manufacturer’s Standard Operating Procedure (SOP) or Guidance for Specification Equivalence established by a bio/pharmaceutical manufacturer.

Both small-molecule and biotherapeutic drug products are in scope of the paper, and the approach applies to release and shelf-life (where applicable) specifications for excipients, drug substances, drug products, and primary packaging containers used by pharmaceutical manufacturers. Microbiological methods are out of scope for this series of papers.

In essence, the authors provide an approach to perform “in-house harmonization” of specifications, or introduction of new methodology, assessing each method and associated acceptance criteria to provide scientific justification that will allow a company to comply with health authority regulations. Therein lies the connection with the PDG concept of harmonization, namely, the same accept/reject decision would be reached regardless of the analytical method employed for that material.

The detailed impacted analytical procedures, associated acceptance criteria, relevant validation packages or method verification packages, method transfers as well as any other generally known information about the methods and then the impacted materials or products must be collected. Each of the two or more methods must first be suitably validated to the current standards described by regulators. It is crucial that the validation package is reviewed for any gaps to current standards; this becomes especially relevant for analytical procedures that were not recently validated or gap assessed. Additionally, if one method was developed and validated by a different laboratory, it is required that the receiving laboratory properly demonstrate it has implemented the method as it was intended to be run (i.e., method verification or transfer). With the two methods suitably validated and verified in a laboratory, it is possible to determine if the methods are comparable or equivalent. Layering in the acceptance criteria associated with each method, it is possible to determine specification equivalence.

As the paper expands on these concepts for assessing specification equivalence, it is important to keep in mind the terms used for analytical methods and their relationship to specification equivalence: method validation, method verification, method comparability and method equivalence. These terms can be confused and have been wrongly used by manufacturers to describe work they have completed. Method validation and method verification have been the subject of confusion. With the adoption of ICH Q2(R2) (5), ICH Q14 (6), and several general chapters in the pharmacopeia (e.g., 

] <1225> and <1226>) some clarity has been provided to industry. The ICH guidance documents will be addressed in a subsequent paper in the series.

Specification equivalence: regulatory guidance

There is not a lot of regulatory guidance provided on the topic of specification equivalence. For analytical procedures, the first part of a specification, there is some guidance provided by the pharmacopoeia. All pharmacopoeias allow, via their General Notices, for the use of “alternative methods” when testing a substance or product by an existing monograph. Use of an alternative method entails risk because of the associated regulatory restrictions of using an alternative method. Specifically in Europe, the 

. General Notices clearly indicate that approval of the competent authority is needed prior to using an alternative method for routine testing. Not receiving this approval places a bio/pharmaceutical manufacturer in a position of non-compliance. Additionally, most global pharmacopoeia General Notices sections include a disclaimer “that in event of doubt or dispute, the analytical procedures of the pharmacopoeia are alone authoritative.” This means that if the alternative method provides a different result than the pharmacopoeia method, the result obtained by the pharmacopoeia method is viewed as the official result.

. has published a first of its kind general chapter, 5.27 Comparability of Alternative Analytical Procedures, which is an informational chapter that became official July 2024. (7) This general chapter’s intent is to provide information to help manufacturers demonstrate that an alternative method is comparable to a pharmacopoeial method. It is stressed in the preamble of the chapter that, “The use of an alternative procedure is subject to authorization by the competent authority. The final responsibility for the demonstration of comparability lies with the user and the successful outcome of the process needs to be demonstrated and documented to the satisfaction of the competent authority” (7). The burden (or risk) of demonstrating comparability is on the manufacturer. However, these requirements are mainly focused on the validation state of the alternative method because pharmacopoeial methods are considered validated to current requirements. After the methods are determined to be of suitable validation status, the chapter indicates that a study where the same samples are tested by both methods should show that the results of the alternative procedure lead to the same unequivocal decision that would be made with the pharmacopoeial procedure. The chapter provides a visual reference of statistical assumptions that should be considered in the data analysis.

FDA issued a draft guidance in July 2015 entitled 

Analytical Procedures and Methods Validation for Drugs and Biologics–Guidance for Indu

stry (8). This guidance is mostly focused on validation parameters of a method and there is a section focused on the use of alternative methods. The information is consistent with the requirements provided by the pharmacopoeia to demonstrate that one method is comparable to another. However, there is no specific guidance provided on method equivalence (i.e., that the same accept/reject decision would result when tested by either method).

Specifications component: analytical procedures

Looking first at the analytical procedures included in the specifications; there are clear requirements from regulators and pharmacopoeias that the analytical procedures are validated and/or verified.

Method validation is the evaluation of the analytical procedure performance characteristics (APPCs) such as specificity/selectivity, sensitivity (at the lower range limit), accuracy, linearity, and range. All these characteristics should be assessed to ensure the method meets the requirements expressed in ICH Q2 (5). These same requirements are also clearly described in section VI B of the FDA guidance referenced previously, which provides more detail on verification activities for non-compendial methods in the same section (8).

Method verification is the assessment of whether the analytical procedure can be used for its intended purpose, under the actual conditions for use for a specified material. Methods must be demonstrated to be suitable for use and applicable under actual conditions of use in the implementing laboratory. A US regulation in the Federal Food, Drug, and Cosmetic Act (FD&C Act) code speaks directly to method verification, namely 21 

) 211.194(a)(2), which states, “suitability of all testing methods used shall be verified under actual conditions of use” (9). The FDA guidance on 

Analytical Procedures and Methods Validation

 provides more detail on verification activities for a compendial method in Section VI, C. (8).

General Chapter 5.26, Implementation of Pharmacopoeial Procedures in the 

 (10) indicates that the implementation of a compendial procedure in a laboratory is a combination of the implementation assessment and the verification assessment. The implementation assessment evaluates if there are any factors associated with the complexity of the procedure and the actual conditions of its use in the implementing laboratory that may affect the performance of the procedure. If any factors are determined to potentially affect the successful implementation, then a verification assessment must be completed. The verification assessment is laboratory work performed to ensure that the procedure is suitable for examination of the article under test, under the actual conditions of use. If the implementation assessment identifies the need for verification experiments, relevant analytical procedure performance characteristics (APPCs) are assessed and verified depending on the intended use of the analytical procedure. A convenient guide is provided for manufacturers to consider when performing verification experiments. Lastly, the general chapter states that these activities should be captured in an appropriate quality system. The requirements to document this activity will be discussed in a subsequent paper in this series.

It should be noted that method validation and method verification activities are carried out for a specific analytical procedure. If multiple analytical procedures are under consideration, the user must ensure that each procedure is validated and verified (if needed). Method validation and method verification are scientific and compliance activities that need to be completed for each of the separate analytical procedures under evaluation as shown in 

. The completion of these two activities for each analytical procedure is necessary before an equivalence study can be undertaken. On the other hand, method comparability and equivalence involve the evaluation of the method validation work completed across multiple analytical procedures as shown in 

Figure 2. Method A’s Validation and Verification are INDEPENDENT of Method B’s Validation and Verification. (Figure courtesy of the authors)

, (3) define method comparability as studies to evaluate similarities and differences in method performance characteristics between two analytical methods (i.e., accuracy, precision, specificity, detection limit, and quantitation limit). In other words, comparability is an evaluation of the method validation results for each method. The comparison of their performance characteristics allows a determination as to whether there are any method limitations or lack of sufficient capability (e.g., limit of quantitation [LOQ] is too high for one method; critical pairs of impurities are not separated, etc.). Determination of differences in the performance characteristics of the methods is important to help identify whether one method is superior to another method but does not allow one to say whether or not the methods can generate equivalent results. That can only be accomplished with a method equivalence evaluation.

Figure 3. Method A directly compared to Method B evaluating differences in Analytical Procedure Performance Characteristics. (Figure courtesy of the authors)

, (3) define method equivalence as studies to evaluate similarities between two analytical procedures regarding generating results for the same sample. In other words, analytical method equivalency evaluates whether the new method can generate equivalent results to those from an existing method. The concepts of comparability and equivalence between analytical methods are illustrated in 

, which shows the applicability across multiple procedures, rather than for one specific procedure. Method equivalence is used to identify the level of risk for not running every method for every test required by every country. In performing method equivalence, understanding the acceptance criteria in relation to the different procedure’s capability is an important consideration to reaching a sound scientific conclusion.

Specifications component: acceptance criteria

Appropriate acceptance criteria are established for a specific pharmaceutical substance or product based on manufacturing capabilities and quality considerations. The acceptance criteria are applicable to the specific analytical procedure used in the determination of material acceptability and within regulatory commitments. When considering different acceptance criteria for different methods, a well-accepted practice is to apply the tightest limits. Choosing the tightest acceptance criteria is a straightforward choice, ensuring that if the result obtained from an analysis meets the criterion, it will comply with all acceptance criteria established for all markets. Readers should be cautioned to ensure that the tightest acceptance criteria make scientific sense and are consistent with the manufacturing process capability for the substance or product and are within the analytical method capability for the substance or product.

However, choosing the tightest limits may not always be possible. If an analytical procedure has a one-sided limit and the second analytical procedure that will be compared to the first procedure has a two-sided limit, using the upper or lower boundary of the one-sided limit may not be practical or scientifically sound.

Method equivalence helps assess the risk of not performing every method for every test required by every country. By trying to do this risk assessment, as mentioned earlier, it is a prerequisite that the user of the analytical procedure ensure that both methods are suitably validated and verified before any method equivalence study is conducted.

The importance of performing method verification, method comparability, and method equivalence cannot be overstated. Failure to adhere to the regulations outlined in 21 

 part 211 has resulted in numerous citations by the regulatory authorities. Since 2010, 21 

211.194(a)(2), which mandates the verification of all testing methods under actual condition of use, has been cited in 155 distinct inspections. Of these, 45 led to Official Action Indicated (OAI) classifications (29%), and 20 escalated to warning letters (12.9%). US 21 

211.165(e), which requires that the accuracy, sensitivity, specificity, and reproducibility of test methods be established and documented in accordance with 211.194(a)(2), has been cited more frequently during the same time frame, appearing in 488 inspections, leading to 131 OAI classifications (26.8%) and 69 warning letters (14.1%) (see 

) (11). Since 2010, the average rates of OAI and Warning Letter issuance associated with any 21 

 Part 211 citation have been 26% and 13.9%, respectively, indicating that inspections citing 21 

211.194(a)(2) are slightly more likely to result in an OAI classification compared to the overall average for 21 

Deficiencies outlined in these warning letters signal critical compliance failures. For instance, DuPont Nutrition USA received a warning letter from FDA (12) in December 2022 after failing to validate and verify its compendial and non-compendial methods for conductivity testing of Avicel, a widely used microcrystalline cellulose excipient. The third deficiency cited in the warning letter underscores the failure to ensure that the test methods used for in-process and release testing were suitable for their intended use. Specifically, the company did not adequately verify its compendial conductivity test method or validate its non-compendial method. Notable deficiencies included the absence of an approved verification protocol, failure to evaluate the accuracy of the method, and a lack of scientific rationale to support the range evaluated during the method verification (i.e., the acceptance criteria were not considered during the company’s evaluation). Additionally, the non-compendial method used for in-process and packaging testing showed a low correlation with the compendial method. Despite this, DuPont released the excipient that failed to meet USP conductivity standards.

In July 2023, Intas Pharmaceuticals Limited received a warning letter from FDA (13) citing critical violations that directly relate to 21 

 211.165(e). One of the key deficiencies noted was the company’s failure to establish the accuracy, sensitivity, specificity, and reproducibility of its test methods. Specifically, Intas did not perform necessary method validation or verification for multiple in-house and compendial methods used in testing of critical raw materials.

Analytical laboratories that perform testing for drug manufacturing facilities are subject to similar regulatory oversight as drug manufacturers. For example, Valisure, a contract analytical lab facility, received a Form 483 from FDA (14) in 2021 for failing to adequately validate and verify several analytical methods used in the testing of pharmaceutical products. Specifically, the firm was cited for failing to document the validation and verification process, establish acceptance criteria, or evaluate the validity of the methods for their intended use. The observation also noted that “the firm failed to verify equivalency” between methods. Following the issuance of the Form 483, Valisure received an untitled letter from FDA in December 2022 (15), which further underscored deficiencies in method validation processes. While Valisure’s testing may not be used for regulatory purposes, FDA expressed concern that the drug manufacturing facilities would use their test results for current good manufacturing practice (CGMP) purposes. This highlights the broader regulatory expectation that both drug manufacturers and contract laboratories must adhere to the validation and verification standards to ensure drug quality.

Similar deficiencies were identified in a FDA Form 483 issued to Hikma Pharmaceuticals USA in June 2024 (16), highlighting issues related to method comparability under 21 

 211.160(b). This regulation requires that laboratory controls include scientifically sound and appropriate test procedures to ensure that drug products conform to established standards of identity, strength, quality, and purity. Regulators cited Hikma for failing to include established key characteristics of method validation, such as accuracy and instrument comparability, in their co-validation process. In addition, the co-validation of the analytical procedure was conducted at Hikma’s Research and Development laboratory, while the original validation was performed by their contracted testing laboratory. Neither validation included justification for excluding key characteristics beyond precision.

 211.165(e) citations since 2010. (Table courtesy of the authors)

Demonstrating specification equivalency appears to be a straightforward task but can be quite complex for bio/pharmaceutical companies to consistently complete. In this paper, several important terms were defined that will be the foundation of additional papers to follow providing a practical approach to specification equivalence. The regulatory risk of not doing appropriate specification equivalency was also demonstrated with recent trending of FDA inspection data. The rate of these observations indicates that more direction for the regulatory expectations is needed for industry. There are some regulatory and pharmacopeial guidance documents available, but the documents remain at a high level in their detail and their approaches. The coming papers will provide an in-depth breakdown on analytical method equivalence, acceptance criteria equivalence, and a process for completing in-house specification equivalence to help eliminate duplicate or redundant testing in laboratories. The next paper in this series will give the bio/pharmaceutical companies decision trees to help determine method equivalence and acceptance criteria equivalence and a process for in-house specification equivalence that could serve as a basis for company’s SOPs.

Specifications: Test Procedures and Acceptance Criteria For New Drug Substances And New Drug Products: Chemical Substances

https://database.ich.org/sites/default/files/Q6A%20Guideline.pdf

Specifications: Test Procedures and Acceptance Criteria for Biotechnological/ Biological Products

https://database.ich.org/sites/default/files/Q6B%20Guideline.pdf

Chambers, D.; Kelly, G.; Limentani, G.; Lister, A.; Lung, K.R.; Warner, E. Analytical Method Equivalency, An Acceptable Analytical Practice, 

Evaluation And Recommendation Of Pharmacopoeial Texts For Use In The ICH Regions

https://database.ich.org/sites/default/files/ICH_Q4B%28R1%29_Guideline_2024_0605.pdf

ICH. Q2 Validation of Analytical Procedures Q2(R2) (ICH, November 2023). 

https://database.ich.org/sites/default/files/ICH_Q2%28R2%29_Guideline_2023_1130.pdf

https://database.ich.org/sites/default/files/ICH_Q14_Guideline_2023_1116_1.pdf

EDQM. General Chapter 5.27 Comparability of Alternative Analytical Procedures. 

Guidance for Industry–Analytical Procedures and Methods Validation for Drugs and Biologics

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/analytical-procedures-and-methods-validation-drugs-and-biologics

General Chapter 5.26 Implementation of Pharmacopoeial Procedures. 

Redica Systems (2024). FDA Citations [Data sourced from Freedom of Information Act (FOIA) responses and the FDA Inspections Citations Details table at 

https://datadashboard.fda.gov/ora/cd/inspections.htm

FDA. Warning Letter to DuPont Nutrition USA Inc. Dec. 2, 2022. 

https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/dupont-nutrition-usa-inc-627211-12022022

FDA. Warning Letter to Intas Pharmaceuticals Limited. Nov. 21, 2023, 

https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/intas-pharmaceuticals-limited-662868-11212023

Redica Systems. Valisure, LLC–Form 483, 2021-07-06, 

https://redica.com/document-store/documents/view/100102186/valisure-llc-form-483-2021-07-06

FDA. Valisure LLC, New Haven, CT 12.5.22 Untitled Letter. FEI 3012063246, 

https://www.fda.gov/media/163682/download

FDA. Hikma Pharmaceuticals USA Inc. Cherry Hill, NJ. 483 issued 06/12/2024. 

https://www.fda.gov/media/179799/download

Joseph A. Albanese is the managing director and consultant with Albanese Consulting, LLC. Gail Reed is senior scientist with Johnson & Johnson. Yelena Ionova is senior manager, Data Strategy and Analytics with Redica Systems. J. Mark Wiggins is owner and compendial consultant with Global Pharmacopoeia Solutions, LLC.

In this first of a four-part series, the authors provide an introduction to a practical approach for establishing specification equivalence.  The regulatory basis and compliance examples from FDA observations and warning letters are included to support the need for an effective process.

Specification Equivalence—A Practical Approach

The increased number and complexity of biotherapeutic products available to patients has spurred a commensurate increase in publicly available quality standards from the pharmacopoeias. These standards, including general chapters, monographs, and physical reference standards, can help guide manufacturers to ensure the identity, strength, quality, and purity of their products. Additionally, the global COVID-19 pandemic has necessitated a swift response from the pharmacopoeias to update existing standards and create new standards and toolkits for their stakeholders. This article highlights recently implemented or ongoing advances from the pharmacopoeias.

) in particular—have published monographs for some biological products since the 1990s, including human insulin, somatropin, interferon, erythropoietin, and vaccines (1). With the bio/pharmaceutical industry’s increased focus on developing complex biotherapeutic products (BTPs), pharmacopoeias have been exploring a variety of approaches for developing public quality standards for these products (2). The status of pharmacopoeia standards for BTPs, including product-specific monographs, performance-based and product class standards, and general chapters, was summarized in an article published in March 2020 (3). The authors now provide an update on the development of these standards over the past two years, serving as a reminder that companies need to stay up to date with evolving pharmacopoeia requirements. The pharmacopoeias’ response to the COVID-19 pandemic is also described.

Resources for COVID-19 from the pharmacopoeias

The COVID-19 global pandemic significantly affected patients, healthcare providers, and the pharmaceutical industry. The pharmacopoeia bodies responded by preparing new or updating currently available information. The US Pharmacopeia (USP) provided two toolkits to stakeholders. The first can be used for assessing vaccine handling and gives cold chain requirements for the messenger RNA (mRNA)-based COVID-19 vaccines (4). The toolkit provides frontline practitioners with the most updated and relevant COVID-19 vaccine information. The toolkit also included a visual inspection guide to help identify falsified COVID-19 vaccines. USP’s second toolkit was focused on the available documentary standards that support vaccine laboratory assessments (5). The second toolkit navigates the documentary standards that are provided by the manufacturing platform rather than product-specific guidance.

Similarly, the European Directorate for the Quality of Medicines and HealthCare (EDQM) made texts from the 

. for vaccine developers available free on their website (6). EDQM also released a guidance on recombinant viral vectored vaccines, which was not available before the pandemic (7). Both USP and EDQM collaborated with other pharmacopoeias (India, Japan, Mexico, World Health Organization, etc.) to work on monographs of potential interest for COVID-19 treatments (8).

USP revised their monographs for alcohol (ethanol and dehydrated ethanol) and isopropyl alcohol due to concerns with possible methanol contamination. Methanol was found in several hand sanitizers used by the public to stop the spread of the virus (9). The revision to add identification testing of methanol was done in response to an FDA request (10) due to the toxicity risk the public faced should methanol be present in the hand sanitizers. This affected most, if not all, bio/pharmaceutical manufacturers that supply the US market with excipients, drug substances, and drug products.

Product-specific monograph development for complex biotherapeutics

Product-specific monographs for complex biologics, such as monoclonal antibodies (mAbs), are still quite rare in pharmacopoeia publications. EDQM published monographs in the 

 for etanercept (11) and infliximab concentrated solution (12) in 2018. Based on the most current work plan (13) for the 

, there are five more product-specific monographs for complex biologics currently being elaborated. The monographs for golimumab concentrated solution and golimumab injection (the first product-specific monograph for a mAb drug product) were published for comment in Pharmeuropa (14). Additionally, a monograph for the TNF-alpha inhibitor adalimumab is being elaborated via the P1 procedure with multiple manufacturers invited to participate in the process (13). Lastly, ustekinumab concentrated solution and ustekinumab injection are the first IL-12/IL-23 inhibitors to be studied by EDQM for monograph development via the P4 process (13).

There are no product-specific mAb monographs currently published in the 

). However, USP has indicated that it is open to begin elaboration of a product-specific mAb monograph, should a company wish to donate the necessary information (15). USP would notify stakeholders through a compendial notice that it is undertaking the elaboration of the donated monograph. This would allow all manufacturers and stakeholders to respond to USP with concerns or to state any objections.

) had begun elaboration of several mAb monographs (16), but to date, no drafts of the monographs have been published for comments. It is expected the monographs will become official in either 

 2020 Supplement 1 (expected 2023) or in 

During the elaboration of the infliximab concentrated solution and etanercept monographs, EDQM recognized that flexibility with methods would be integral to the useability of the monographs. The production section of the product-specific monographs contains a key test for glycans or N-Glycans for either infliximab or etanercept, respectively. EDQM introduced the method published in the monograph with the following language: “The following procedure is given as an example” (12). This approach was used because a manufacturer could employ a variety of method techniques to meet a requirement as allowed in 

general monograph— “Monoclonal Antibodies for Human Use (2031).”

The phrase “for example” was originally defined in a technical guide from EDQM but could be easily misinterpreted as a requirement rather than a suggestion. EDQM has now added a definition of “for example methods” to the General Notices in the 

, explaining the intent and compliance expectations for a method of this type (17). The addition of the definition to the General Notices is a significant and welcome change for stakeholders. The revised General Notices clearly explain that monographs containing the statement, “The following procedure is given as an example,” indicates the method has been validated for its intended purpose. A manufacturer may choose to implement the “for example” method as written with appropriate verification on its product, or it may use a suitably validated procedure that is approved by the competent authority. If using a different method than the “for example” method, the manufacturer does not have to show the equivalence of its suitably validated method to the “for example” method.

First “horizontal standard” for biotherapeutic monographs

Today, there are several TNF-alpha inhibitor products available, and manufacturers have used a wide variety of methods to assess the potency of these mAbs. EDQM has completed a multi-lab evaluation wherein four approved bioassay methods for specific products were studied to determine their respective suitability for the entire class of TNF-alpha antagonist products (18). The result of these studies has produced a new general chapter: “Cell-based Assays for Potency Determination of TNF-alpha Antagonists (2.7.26)”. The general chapter will become official in 

 volume 11, supplement 1 (official date: April 2023).

This general chapter is referred to as a horizontal standard, meaning the content of the chapter is widely applicable to multiple product-specific monographs. The general chapter provides manufacturers with the flexibility to choose from the four assay types presented in the chapter or use a different cell-based assay (with the approval of a competent authority). Two product-specific monographs (etanercept and infliximab concentrated solution) have been updated to indicate the example procedure would be the specific cell-based assay originally used and that the other three cell-based assay test procedures in 2.7.26 that were verified by the study are also suitable for specific products (18).

This is the first of three horizontal standards that EDQM intends to elaborate and make official. Two other horizontal standards are currently being elaborated by EDQM: “Capillary Isoelectric Focusing for Recombinant Therapeutic Monoclonal antibodies (2.5.44)” and “Size Exclusion Chromatography for Recombinant Therapeutic Monoclonal Antibodies (2.5.43)” (19).

EDQM has either updated or is currently revising several 

general chapters that will be applicable for emerging cell and gene therapy (CGT) products that are being approved and developed (20). The general chapter, “Gene Transfer Medicinal Products (GTMPs) for Human Use (5.14),” is being divided into a general monograph, “Gene Therapy Medicinal Products for Human Use (3186)” and a new general chapter “Additional Information on Gene Therapy Medicinal Products for Human Use (5.34).” The general monograph provides new information for genetically modified autologous human cells and oncolytic herpes simplex virus for human cells. Additionally, information related to the definition, general requirements on the production of GTMPs, recombinant vectors, and genetically modified cells previously found in the general chapter (5.14) has been revised for inclusion in the general monograph. The new general chapter provides new information for genetically modified bacterial cells for human use and updated requirements for retroviridae-derived vectors for human use.

The final change to CGT standards is to general chapter “Raw Materials of Biological Origin for the Production of Cell-based Therapy Medicinal Products (5.2.12).” The chapter is under revision to indicate it is no longer a stand-alone, and vector requirements will now reference the new general monograph 3186.

 published a best practice guidance for Advanced Therapy Medicinal Products (ATMP) Flow Cytometry and Vector Copy Number (21). The guidance addresses the complexity and risk associated with each stage of assay development of advanced therapy medicinal products. The guidance offers a practical and phase appropriate validation tool to help ensure the success of a manufacturer’s CGT program.

Biologics, oligonucleotides, and performance standards

USP has manufactured four mAb performance standards and has made them available for purchase (22). These mAb standards have molecular weights between 146K and 150K daltons with different isoelectric points and can be used as system suitability controls in a variety of commonly used methods for mAb analysis, such as charged variants, molecular weight determination, and glycosylation. The development of the standards was driven by stakeholder engagement sessions led by USP. USP indicates that these standards can be reliably and reproducibly manufactured to ensure a long-term supply and can serve as a control for a newly developed assay.

Additionally, USP is focusing on the development of oligonucleotide-related standards (performance standards) for raw materials (23). Phosphoramidites are the target for initial standard development due to their criticality to the supply of this emerging therapeutic class. Five performance standards are characterized by mass spectrometry and 

H NMR. These performance standards can be used for controlling and monitoring reactive impurities in phosphoramidites.

As more biotherapeutics products come to market, it is important for manufacturers to ensure their products comply with current pharmacopoeial standards, which are constantly evolving. The new and revised quality standards published by the world’s pharmacopoeia serve to ensure patients receive drug products of the appropriate identity, strength, quality, and purity. Manufacturers can expect that these new standards will continue to be elaborated for the foreseeable future, and it is critical that they maintain a surveillance process to identify and assess the changes as they happen.

J.M. Wiggins and J.A. Albanese, “Monograph Development: Why and When to Participate,” 

Pharmaceutical Technology Regulatory Sourcebook 

J.M. Wiggins and J.A. Albanese, “Monograph Development: How to Participate; How to Harmonize,” 

J.M. Wiggins and J.A. Albanese, “Pharmacopoeia Compliance: Putting It All Together; What Is on the Horizon,” 

 Regulatory Sourcebook eBook, 34–42 (March 2020).

USP, “COVID-19: Addressing the Global Health Crisis,” 

EDQM, “Free Access to Supportive Pharmacopoeial Texts in the Field of Vaccines for Human Use during the Coronavirus Disease (COVID-19) Pandemic,” 

EDQM, “Recombinant Viral Vectored Vaccines For Human Use,” 

EDQM, “EDQM Initiatives in the Context of COVID-19 Vaccines and Therapies,” 

Policy for Testing of Alcohol (Ethanol) and Isopropyl Alcohol for Methanol, Including During the Public Health Emergency (COVID-19), Guidance for Industry

 monograph for Etanercept (2895)–to be published soon in Supplement 9.5,” 

EDQM, “New Monograph For Infliximab Concentrated Solution: The First Monograph on a Monoclonal Antibody in the 

EDQM, “New Nonograph on a Single-source Anti-TNF-alpha Monoclonal Antibody Released for Public Consultation in Pharmeuropa,” 

“Questionnaire on materials collection for the development of monoclonal antibody national standard and mAb pharmacopoeia monograph drafting related issues,” Surveillance and translation provided by the R&D-Based Pharmaceutical Association Committee (RDPAC) of the China Association of Enterprises with Foreign Investment (CAEFI), April 2019.

Getting the Big Picture: What has Changed in the Ph. Eur. General Notices”

. Commission Adopts First ‘Horizontal Standard’ for Monoclonal Antibodies,” Press Release, May 18, 2022.

. Activities in the Field of Biologics: an Update from the EDQM,” Presentation at the New Jersey Pharmaceutical Quality Control Association, Summer Meeting, June 21, 2022.

EDQM, “Publication of the general monograph Gene therapy medicinal 

products for human use (3186) and the general chapter Additional information on gene therapy medicinal products for human use (5.34) in Pharmeuropa 34.3”, Explanatory Document.

Advanced Therapy Medicinal Products Guidance–Flow Cytometry and Vector Copy Number, Guidance

USP, “New Applications for mAb Reference Standards: Resolving Charge Variants,” 

K. Carrick, “USP Biologics Overview”, Presentation at the New Jersey Pharmaceutical Quality Control Association, Summer Meeting, June 21, 2022.

Joseph A. Albanese is the managing director and consultant with Albanese Consulting, LLC. J. Mark Wiggins is the owner and compendial consultant with Global Pharmacopoeia Solutions, LLC.


Volume 46, Number 10
October 2022
Pages: 56–58

When referring to this article, please cite it as J. A. Albanese and J. M. Wiggins, “Biologic Standards in the Pharmacopoeias: An Update,” 

Awareness of recently implemented—or ongoing—advances by the pharmacopoeias can help biotherapeutic manufacturers remain compliant with current requirements.

Biologic Standards in the Pharmacopoeias: An Update

Compliance with requirements published by pharmacopoeias around the world is a legal and regulatory requirement in those countries and regions in which the pharmacopoeia is applicable. This fundamental principle is presented at the beginning of a series of 12 articles (1–12) published to increase the understanding of this far-reaching and complex situation and to give practical guidance on addressing pharmacopoeia compliance. The articles appear in three online Regulatory Sourcebook eBooks and can be accessed through a dedicated webpage (13) with individual links to each of the 12 articles.

The detailed information in the articles provide important compliance considerations for the bio/pharmaceutical industry, including innovator, generic-drug, virtual, and start-up companies who discover, develop, manufacture, and distribute small-molecule drug products, biotherapeutic products, and vaccines, as well as the drug substances and excipients used in these products.

This current article provides an overview and summary of key points from the series—in effect, a narrative table of contents—intended to bring greater awareness to the availability of the articles, which can help provide guidance for this important pharmacopoeia compliance work.

Why Pharmacopoeia Compliance Is Necessary

The first article in the series (1) provides the legal and regulatory basis for the fundamental principle of pharmacopoeia compliance in the United States, Europe, Japan, and many other countries, thereby establishing the foundation for subsequent articles in the series. The purpose and content of pharmacopoeias is presented, and it is noted that the pharmacopoeias impact drugs and their ingredients throughout the entire product lifecycle. Additional important points are also introduced: a company must comply with “current” pharmacopoeia requirements, meaning a company must monitor and implement updates published by the pharmacopoeias; and a company must comply with applicable pharmacopoeia requirements and also with their approved drug product registrations, so that a company must address the complexity of these compliance challenges. The information provided in the first article is useful for enabling engagement and discussion among the many stakeholders within a company who are impacted by pharmacopoeia requirements, ensuring a common understanding across the various functions, and helping to avoid the risks associated with non-compliance.

Why Pharmacopoeia Compliance Is Difficult

The second article (2) provides a comprehensive, end-to-end framework to help bio/pharmaceutical companies better understand the external and internal challenges that make pharmacopoeia compliance difficult. Among the external challenges are the lack of broad harmonization of pharmacopoeia requirements around the world and the significant number of new and revised requirements that are routinely published. Internal challenges for companies include the lack of broad understanding of the need for and the complexity of remaining compliant. Enhanced awareness provided by the second article can facilitate the establishment and maintenance of collaborative partnerships among internal stakeholders to help address the compliance challenges.

A Brief History of Pharmacopoeias: A Global Perspective

Today, there are as many as 40 pharmacopoeias published around the world. Their history, presented in the third article of the series (3), reveals a common purpose, which is to support the health of the population through consistent standards for medicines. Many, including the 

, were established to harmonize the content and remove inconsistencies between the various pharmacopoeias which then existed. Regional and international initiatives continue even today, with global pharmacopoeia standards being one potentially beneficial outcome. The global and historical perspective is helpful in understanding the complexity and challenges of pharmacopoeia monitoring and compliance.

Global Pharmacopoeia Standards: Why Harmonization Is Needed

Building on information in prior articles, the fourth article (4) provides some industry perspective on the benefit of harmonization or convergence of pharmacopoeia standards around the world. When the standards are not aligned, the differences increase the cost and complexity of compliance. The concepts of the “ideal pharmacopoeia” and “compendial globalization” are presented as potential models to help achieve consistent and appropriate quality requirements for medicines worldwide. Concluding the fourth article, readers are asked to imagine a world where there is no need for translation, because the pharmacopoeias are all saying the same thing. Global pharmacopoeia standards would help to support the availability of medicines with consistent quality for patients worldwide.

Harmonization Efforts by Pharmacopoeias and Regulatory Agencies

There are many pathways to achieve harmonization, and several approaches are currently underway. The pharmacopoeias and regulatory agencies around the world, in collaboration with their stakeholders, have been actively and successfully working toward harmonization for quite some time. The fifth article in the series (5) describes what has been achieved in this area so far and what is yet to come. Among the topics covered are the Pharmacopoeial Discussion Group and the International Council for Harmonization (ICH), with particular attention given to the ICH Q3 topic on impurities and Q4B on the interchangeability of selected pharmacopoeia text. Contributions of the World Health Organization are also described, which include their convening of the International Meetings of World Pharmacopoeias and the resulting establishment of Good Pharmacopoeial Practices to encourage harmonization of compendial standards. Also discussed is the successful collaboration between the bio/pharmaceutical industry and the pharmacopoeias to achieve prospective and informal harmonization of new monographs for drug substances and products.

Revision Process for Global/National Pharmacopoeias

As noted in the first article (1), a company must comply with “current” compendial requirements, which introduces the need to monitor and implement updates published by the pharmacopoeias. The revision processes used by the pharmacopoeias and their associated schedules for publication of proposed and official updates are detailed in the sixth article (6). Designating pharmacopoeias as either “global” or “national”, based on regulatory acceptance, can help give visibility to some of the differences between their processes. This in turn can assist individual companies in focusing their compendial work on those activities that help ensure compliance.

Surveillance Process for Industry: Monitoring Pharmacopoeia Revisions

The surveillance process used by the industry is driven by the revision process and publication schedules of the pharmacopoeias. The seventh article in the series (7) takes a detailed look at industry processes to monitor the significant volume of changes published and to achieve on-time compliance with updated requirements. Monitoring the pharmacopoeia updates provides an opportunity to respond to proposed changes and provide input that may potentially impact the decision on whether and how the updates proceed. Practical guidance is presented in the context of a compendial affairs organization within a bio/pharmaceutical company. There is also an exploration of the additional people and tools necessary to establish effective, efficient, sustainable, scalable, and successful processes for addressing the challenges of pharmacopoeia compliance.

Monograph Development: Why and When to Participate

As noted above, responding to proposed updates in the pharmacopoeias provides an opportunity for a company to potentially influence the outcome. There is an opportunity for even more proactive advocacy through a company’s participation in the process to develop new and revised monographs. The eighth article of the series (8) presents many considerations to aid a company in determining whether or not to submit a monograph proposal. Additional considerations are provided on the most appropriate timing for a submission, from the perspective of both the pharmacopoeia and the company. The potential for achieving harmonized monographs is also discussed. The article makes it clear that the answers to these questions on monograph development may not be the same for all companies, or products in the portfolio.

Monograph Development: How to Participate; How to Harmonize

Having explored in the eighth article (8) the considerations of whether and when a company should submit a monograph, once decided, there are additional practical points to consider. These include how to navigate the process of working with a pharmacopoeia and how to approach prospective or informal harmonization of the monograph through collaboration with multiple pharmacopoeias. These additional points are described in the ninth article (9), which also includes detailed considerations of which groups in a company should have the responsibility to submit the monograph and what specific information and materials are necessary to support monograph development. Taken together, the eighth and ninth articles provide a comprehensive set of tools to enable a company to understand and successfully execute the monograph development process.

A Practical Approach to Pharmacopoeia Compliance

Compliance with pharmacopoeia requirements that are applicable in a particular country, and also with product registrations as approved in countries around the world, is a significant challenge for bio/pharmaceutical companies. Effectively addressing differences between the pharmacopoeia and approved registrations can be complex. The tenth article of the series (10) tackles the specific compliance challenge that occurs when a new monograph is published in the pharmacopoeias for a drug substance or drug product in the company’s portfolio. Possible options are provided to deal with differences in limits and methods between the monograph and the previously approved registration. This practical guidance can help a company align on the best overall compliance strategy for a given situation.

A Case Study in Pharmacopoeia Compliance: Excipients and Raw Materials

The tenth article (10) dealt with externally based compliance challenges, driven by decisions made by the pharmacopoeias during the monograph development process. There are other compliance challenges that are internally based, resulting from decisions made by one functional area in the company without consideration of the broader impact to other functional areas throughout the organization. One such example can be found with raw materials and excipients, where a consistent, cross-functional approach is needed to ensure the appropriate selection, sourcing, testing, and filing of the materials used to manufacture bio/pharmaceutical products in a global environment. This case study is explored in the eleventh article (11), with principles and strategies provided to help companies ensure compliance with applicable pharmacopoeia and regulatory requirements.

Pharmacopoeia Compliance: Putting It All Together; What Is on the Horizon

The final article of the series (12) attempts to summarize and pull all the various threads of the individual articles together into one consolidated picture of pharmacopoeia compliance. A holistic view is provided for the roles, responsibilities, activities, and other considerations, which are necessary to ensure compliance across the bio/pharmaceutical industry. The article continues with a look ahead at topics that will likely result in further evolution in the pharmacopoeias around the world. Some of the future trends explored are: new approaches to specifications, including those for complex biotherapeutics; the use of analytical quality by design and continuous manufacturing; concerns with impurities, such as N-Nitrosamine contamination; and the growing importance of national pharmacopoeias from around the world, for example those in China, Russia, and Brazil. This look into what is on the horizon can help companies prepare for the inevitable changes in the pharmacopoeias and ensure the continued supply of quality medicines to patients globally.

The need for pharmacopoeia compliance and the challenge of achieving it are explored in detail throughout the series of articles, which are intended to bring greater visibility and understanding of this fundamental principle to the bio/pharmaceutical industry. The articles present many facets of the processes, people, and tools necessary for a company to comply with the pharmacopoeia as well as their approved drug product registrations. The articles reflect the continuing evolution of the pharmacopoeias, their requirements, and the need for harmonization to achieve truly global standards.

Along with the understanding and assistance provided to those who perform the work, the articles have the additional goal of helping to ensure the continued availability of medicines with consistent quality. Meeting the necessary compliance requirements for these medicines ensures meeting the needs of patients around the world, regardless of where the patients live, where the medicines are manufactured, or which pharmacopoeias may apply.

The authors gratefully acknowledge the contribution of Susan J. Schniepp for her technical review and helpful suggestions during the preparation of this series of articles.

Pharmaceutical Technology Regulatory Sourcebook eBook

Why Pharmacopoeia Compliance Is Difficult,

Surveillance Process for Industry: Monitoring Pharmacopoeia Revisions,

,” Pharmaceutical Technology Regulatory Sourcebook eBook, 14–23 (March 2020).

A Practical Approach to Pharmacopoeia Complianc

Processes, people, and tools are needed to comply with the pharmacopoeia and approved drug product registrations.